Schwartz W J
Department of Neurology, University of Massachusetts Medical School, Worcester 01655.
J Biol Rhythms. 1991 Summer;6(2):149-58. doi: 10.1177/074873049100600205.
We previously reported the results of an experimental paradigm in which tetrodotoxin (TTX) was chronically infused by miniosmotic pump into the rat suprachiasmatic nuclei (SCN) (Schwartz et al., 1987). Although TTX reversibly blocked photic entrainment and overt expression of the circadian drinking rhythm, the circadian pacemaker in the SCN continued to oscillate unperturbed by the toxin, and we concluded that Na(+)-dependent action potentials are not a part of the SCN pacemaker's internal timekeeping mechanism. In the research reported in the present paper, we used our paradigm to chronically infuse other agents, in order to evaluate the validity of this interpretation further. (1) Infusion of 50% procaine into the SCN of blinded rats resulted in a disorganized circadian drinking rhythm during the infusion, after which behavioral rhythmicity returned without apparent phase shift. In intact rats, procaine reduced the phase-resetting action of a reversed light-dark cycle imposed during the infusion. Thus, the effects of voltage-dependent Na+ channel blockade by a local anesthetic resemble those produced by TTX. (2) Infusion of high (20 mM) K+ or 100 microM veratridine into the SCN of blinded rats resulted in an apparent phase advance of the circadian drinking rhythm by over 4 hr. The phase-shifting effect of veratridine was blocked by simultaneous infusion of 1 microM TTX. Thus, membrane depolarization or direct activation of voltage-dependent Na+ channels can affect the pacemaker's oscillation. Our infusion paradigm can detect alterations of rhythm phase, and the lack of phase shift after TTX or procaine infusion is not an artifact of an insensitive method.
我们之前报道了一种实验范式的结果，其中通过微型渗透泵将河豚毒素（TTX）长期注入大鼠视交叉上核（SCN）（施瓦茨等人，1987年）。尽管TTX可逆地阻断了光诱导以及昼夜节律性饮水节律的明显表达，但SCN中的昼夜节律起搏器继续振荡，不受毒素干扰，并且我们得出结论，依赖钠离子的动作电位不是SCN起搏器内部计时机制的一部分。在本文报道的研究中，我们使用该范式长期注入其他药剂，以便进一步评估这种解释的有效性。（1）向失明大鼠的SCN中注入50%的普鲁卡因，在注入期间导致昼夜节律性饮水节律紊乱，之后行为节律恢复，没有明显的相位偏移。在完整大鼠中，普鲁卡因降低了注入期间施加的反向明暗循环的相位重置作用。因此，局部麻醉剂对电压依赖性钠离子通道的阻断作用类似于TTX产生的作用。（2）向失明大鼠的SCN中注入高浓度（20 mM）的钾离子或100 microM的藜芦碱，导致昼夜节律性饮水节律明显提前超过4小时。藜芦碱的相位偏移作用被同时注入1 microM的TTX所阻断。因此，膜去极化或电压依赖性钠离子通道的直接激活可以影响起搏器的振荡。我们的注入范式可以检测节律相位的改变，并且TTX或普鲁卡因注入后缺乏相位偏移不是一种不敏感方法的假象。
